SIRT1 is a NAD(+)-dependent deacetylase. It deacetylates a broad range of substrates and is involved in multiple diseases such as type 2 diabetes and cancer. Here we discovered a new class of SIRT1 inhibitors with the scaffold of 3-(furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The inhibitors up-regulate acetyl p53 level in human breast cells MCF-7. The docking simulations indicated that the scaffold and the R-substituents of the inhibitors bind in the C and D pocket of SIRT1, respectively, which was supported by the structure-activity relationship and SIRT1 mutagenesis studies. We propose that binding of the inhibitors repels the entering of the nicotinamide moiety of NAD(+) to the C pocket, prevents its transformation to the productive conformation and therefore inhibits the deacetylation catalyzed by SIRT1.
Keywords: 3-(Furan-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole derivatives; Deacetylation; Inhibitor; Protein–ligand interaction; SIRT1; Structure–activity relationship.
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